RETRACTED ARTICLE: Radiation Sialadenitis Induced by High-dose Radioactive Iodine Therapy

Abstract

Radioactive iodine (¹³¹I) is accumulated in the thyroid tissue and plays an important role in the treatment of differentiated papillary and follicular cancers after thyroidectomy. Simultaneously, ¹³¹I is concentrated in the salivary glands and secreted into the saliva. Dose-related damage to the salivary parenchyma results from the ¹³¹I irradiation. Salivary gland swelling and pain, usually involving the parotid, can be seen. The symptoms may develop immediately after a therapeutic dose of ¹³¹I and/or months later and progress in intensity with time. In conjunction with the radiation sialadenitis, secondary complications reported include xerostomia, taste alterations, infection, increases in caries, facial nerve involvement, candidiasis, and neoplasia. Prevention of ¹³¹I sialadenitis may involve the use of sialogogic agents to hasten the transit time of the radioactive iodine through the salivary glands. However, studies are not available to delineate the efficacy of this approach. Treatment of the varied complications that may develop encompass numerous approaches and include gland massage, sialogogic agents, duct probing, antibiotics, mouthwashes, good oral hygiene, and adequate hydration. Recently interventional sialoendoscopy has been introduced an effective tool for the management of patients with ¹³¹I-induced sialadenitis that is unresponsive to medical treatment.

Introduction

Short-term and long-term complications of radioactive iodine (¹³¹I) therapy for patients with differentiated thyroid cancer are well known. Radiation damage to the salivary glands is one of the most common complications [1–4]. This morbid aspect of ¹³¹I therapy has caused significant patient distress and warrants measures designed to circumvent this commonly experienced salivary gland impairment. Consequently, this paper will review the mechanisms involved in the evolution of sialadenitis and the therapeutic steps that can be taken to inhibit or limit its onset, or treat the condition if it develops.

Salivary Glands and Uptake of the Radioactive Iodine

The salivary glands also have the capacity to concentrate iodide selectively for unknown reasons (Fig. 1). The iodide is then secreted into saliva such that its salivary concentration has been reported to vary from 20 to 100 times that found in the serum [5–10]. It is this critical ability that causes glandular damage when ¹³¹I is used. The principal site of the iodide transport into saliva is the epithelium of the parotid salivary gland’s intralobular ducts [11, 12]. Iodide is extracted from periductal capillaries and concentrated by the ductal epithelium, whereupon it is secreted into the duct lumen and transported into the oral cavity. It has been calculated that up to 24% of the administered ¹³¹I dose for thyroid cancer therapy is lost in the saliva [13].

Fig. 1.

Anterior (a) and left lateral (b) head and neck planar views of post-ablation scintigraphy in patients who underwent total thyroidectomy due to thyroid carcinoma. Normal physiologic uptake of radioactive iodine by the salivary glands is indicated. (blue arrows: parotid glands; red arrows :submandibular glands). Purple arrow indicates accumulation of radioactive iodine in the oral cavity. Black arrow indicates radioactive iodine uptake in remnant thyroid tissue

The salivary gland is mainly composed of serous and mucous cells. The composition of the serous and mucous cells differs among salivary glands [5, 6]. The parotid gland is mainly composed of serous cells. The sublingual gland is mainly composed of mucous cells, and the submandibular gland contains mixed mucous and serous cells. Serous cells are particularly concerned with secretion of salts and zymogen, the precursor of amylase. The mucous cells secrete mucin, a lubricant that eases swallowing and acts as a protective oral mucosal barrier. In the process of concentrating the radioactive iodine, the salivary glands are exposed to the damaging effects of irradiation. Therefore, serous and mucous cells are susceptible to the deleterious effects of ionizing radiation [5, 14].

The ¹³¹I irradiation of the salivary glands also causes endothelial damage to the glandular vasculature [9]. An increase in capillary permeability results in the leakage of plasma proteins and electrolytes into the surrounding interstitial tissues. The simultaneously injured irradiated intralobular ducts lose their ability to filter and prevent plasma proteins from entering the saliva. As a result of these two mechanisms, elevated protein values are evident in parotid saliva [9, 15]. Elevated sodium and chloride levels are also found in parotid saliva because a radiation-damaged duct does not have the normal duct’s ability to resorb these electrolytes secreted by the terminal acinar cells as saliva progresses through the duct system. Furthermore, salivary phosphate levels are decreased when the damaged epithelium of the intralobular duct’s wall fails in its normal function to transport phosphate into the saliva. Biochemical changes in saliva can be expected in all patients receiving therapeutic ¹³¹I [9, 10], the extent of which is obviously dose dependent.

Early and Late Sialadenitis

Sialadenitis is the most frequent complication of ¹³¹I therapy for thyroid cancer. Almost immediately after ¹³¹I therapy, transient swelling and pain with decreased salivary flow, usually bilateral and involving the parotid glands, are known to become a problem [1, 4, 5, 16–19]. The radiation-induced swelling from the inflammatory infiltrate causes increased periductal pressure with duct constriction. This results in salivary retention and adds to the swelling and pain. Within a few days, resolution of this post-therapeutic inflammatory process occurs and symptoms subside [18, 20].

Initially, not all salivary glands were thought to be impaired, while those glands that demonstrated damage seemed to heal spontaneously without further subjective and objective symptomatology. Such assumptions probably derived from the observation that the initial and immediate parotid swellings were transient in nature. Numerous reports of permanent harm and the associated symptomatology have been reported [10, 21–23]. Allweiss et al. [8] reported that 10 of 87 patients (11.5%) returned on their own volition over various periods of time with complaints compatible with chronic sialadenitis after ¹³¹I therapy. Alexander et al. [24] examined 203 patients within 3 months of ¹³¹I therapy (100–200 mCi) and found that 67 patients (33%) had symptoms of sialadenitis, usually manifesting as bilateral parotid swelling. Thirty-one of the 67 patients also had submandibular gland swellings. One year later, persistent salivary complaints were present in 87 of the patients. The longer elapsed time allowed for continued progression of gland degeneration.

The first gland symptom that prompts a voluntary post-¹³¹I therapy visit is usually obstructive in nature. Duct lumen narrowing from inflammatory stricturing is instrumental in the formation of a jelly-like plug. The plug results when a nidus of radiation-induced inflammatory cells and/or the narrowed duct lumen creates an obstruction with stagnation and mucus precipitation. Obstructive symptomatology with swelling and pain will then develop from salivary retention, most marked during periods of increased salivary production (eating). Because the plug is soft, increased retrograde pressure eventually results in its spontaneous extrusion and the symptoms subside. Simultaneously, the patient becomes aware of a salty taste because the intralobular ducts have not adequately resorbed sodium and chloride ions from the saliva. Furthermore, because salivary lavage is impeded, an orally ascending secondary duct infection can develop and lead to an intensification of the obstructive symptoms of swelling and pain. Continued exacerbations, facilitated by the scarred duct wall and decreased salivary lavage, can be expected.

Diagnosis of chronic sialadenitis can readily be accomplished when the patient’s history of having received radioactive iodine is factored into the patient’s clinical symptomatology. Computerized tomography scans, in an attempt to identify sialoliths, almost certainly will be negative. Because parotid stones are uncommon, this procedural approach is not cost effective. Evaluation of gland function is accomplished via a salivary gland scintigraphic examination with technetium-99m pertechnetate (TPT). TPT is effectively concentrated and secreted by salivary gland tissue, thus affording the opportunity to study gland function in real-time. The effects of ¹³¹I on the parenchyma and on the excretory ducts are independent of each other. Abnormal parenchymal uptake, duct secretory clearance or both (Fig. 2) were observed with a salivary gland scintigraphy in 73% of patients who received an average of 13,875 MBq (375 mCi) ¹³¹I and whose dose-related symptoms became evident over a period of several months [25]. Initially, TPT uptake in the salivary gland may be normal. But TPT clearance is delayed resulting in increased TPT retention because of early damage to the duct wall. Later, diminished TPT uptake results from vascular fibrosis caused by the destructive effect of the ¹³¹I and becomes manifest slowly over a prolonged period. Several studies using salivary gland scintigraphy have revealed that dosages of 18,500 MBq (500 mCi) caused abnormal salivary gland function in as many as 80% of the patients [26] and approached 100% when more was used [27–29]. Several reports revealed good correlation between subjective symptoms and objective findings of salivary gland scintigraphy [30–32]. Raza et al. [30] reported 69% of the symptomatic patients were also scintigraphic positive. Although most patients with reduced salivary gland function reported xerostomia, a few had no symptoms. The absence of subjective symptoms in these patients was probably a result of the compensatory function of the other salivary glands.

Fig. 2.

Anterior, right lateral and left lateral images of salivary scintigraphy at 20 min after injection of technetium-99m pertechnetate (a) and 10 min after ingestion of sialagogues (b). Normal technetium-99m pertechnetate uptake is shown in both parotid and submandibular glands and normal clearance of accumulated technetium-99m pertechnetate

As can be anticipated, the effect is dose related. Several previous studies reported a higher number of cumulative treatments were associated with increased risk of salivary gland side effects from ¹³¹I therapy [8, 19, 24, 25, 31]. In single-dose radioiodine therapy, the risk of persistent salivary gland side effects is increased at administered doses of more than 11,100 MBq (300 mCi) [32, 33]. Persistent salivary gland side effects developed in a few patients with ablation doses of radioiodine. Acute salivary gland side effects developed in 6.9–33% of patients with single dose ¹³¹I ablation [32–35]. They demonstrated a dose-response relationship between administered amount of radioiodine and salivary gland side effects. Grewal et al. [36] also reported administered doses of more than 2,775 MBq (75 mCi) were associated with more salivary gland side effects than administered doses of approximately 1,110 MBq (30 mCi).

Although the side effects tended to be associated with increasing administration, it is clear that in many patients given relatively large radioiodine doses, salivary gland side effects developed only minimally. Furthermore, even with rather small doses, significant salivary gland side effects developed in some patients. Therefore, important variables other than the dosage must play a major role in the likelihood of salivary gland side effect development. These variables could include a difference in radiation sensitivity, actual dose to the salivary glands, hydration status, and use of sour candies or nonsteroidal inflammatory medications not reported to the treating physician. Future studies will be required to answer these questions.

The function of the parotid glands was affected more often than that of the submandibular glands. Albrecht and Creutzig [26] reported involvement of the parotid glands in 59% of cases and of the submandibular glands in 16% after ¹³¹I therapy. There are at least two hypotheses regarding the apparent difference in radiosensitivity between the parotid and submandibular salivary glands [25, 37, 38]. The first is related to anatomical differences between the two glands. Specifically, the parotid gland mainly contains serous cells, whereas the submandibular gland consists of a mixture of serous and mucinous cells. Because the mucinous-secreting glands increase their secretion rate after irradiation, the submandibular gland is deemed to be less radiosensitive than the parotid glands. The second hypothesis is based on the difference in the kinetics of the two types of salivary glands, i.e., the submandibular glands have a higher continuous unstimulated secretion than the parotid gland, possibly reducing sensitivity. The measured absorbed dose cannot explain the apparent difference in radiosensitivity (absorbed dose to the submandibular gland is evidently higher than that to the parotid gland) and thus corroborates the hypothesis that the differences in radioiodine secretion and cell composition between the parotid and submandibular salivary glands have a predominant impact on relative radiosensitivities.

In the last several years, recombinant human thyroid stimulating hormone (rhTSH) was approved for use in ¹³¹I ablation of thyroid cancer patients without evidence of distant metastasis in both Europe and the US. As would be expected, ¹³¹I is cleared from the blood and body more rapidly after rhTSH preparation than after traditional thyroid hormone withdrawal (THW) [39, 40]. Because the side effects of ¹³¹I may be related both to administered treatment and to cumulative dose, it would be considered that the more rapid blood and whole-body clearance of ¹³¹I associated with rhTSH preparation for ¹³¹I ablation is associated with a decrease in radiation exposure to the salivary glands and potentially less salivary gland dysfunction than with traditional THW. A study by Rosario et al. suggests that the early, transient salivary gland symptoms developing within the first week after ¹³¹I ablation were less commonly seen after preparation with rhTSH (30%) than after preparation with THW (58%). However, the risk of persistent pain or xerostomia was similar in both groups (3% with rhTSH and 4.6% with THW) [41]. Therefore, it is possible that rhTSH-assisted remnant ablation may be associated with less early, transient toxicity than THW. However, the risk of a long-term, persistent effect appears to be similar between rhTSH and THW. Grewal et al. [36] also reported that preparation with rhTSH had a higher risk of later onset salivary gland swelling than preparation with THW. These results suggest the more rapid clearance of ¹³¹I from blood and body seen with rhTSH preparation was not associated with a decrease in the risk of salivary gland pain or swelling, dry mouth, or alterations in taste.

Secondary Complications

Taste

Often, immediately after ¹³¹I ingestion for thyroid cancer, transient taste alterations develop concurrently with the initial but temporary parotid symptomatology. Distorted taste perception has been reported in 16% of the patients who received 5,550 MBq (150 mCi) ¹³¹I, [27] and 27% of those who received 7,400 MBq (200 mCi) ¹³¹I, [24], and may last several weeks. Grewal et al. [36] report altered taste developed in 13% of the patients who received radioiodine ablation and resolved in 91% of the patients (median time to resolution: 9 months). With higher therapeutic doses of ¹³¹I, the loss of taste can occasionally become permanent. The explanation for taste dysfunction rests mostly with von Ebner’s serous glands, which are situated in the immediate vicinity of the taste bud-containing circumvallate papilla. As with all salivary serous acini, radioactive iodine also hones in on the von Ebner's glands and creates a radiation sialadenitis with a diminished ability, albeit often temporary, of these structures to secrete serous saliva. Salivary fluid from von Ebner’s glands functions to carry the food chemicals that facilitate taste to taste buds. With the loss of this salivary transport, the ability of the chemical tastants to activate the taste buds is inhibited. Furthermore, a damaged duct’s inability to adequately resorb salivary sodium and chloride ions results in a salty taste and plays into the mix of altered taste.

Facial Nerve

Levinson et al. [10] reported two patients who rapidly developed transient facial paralysis after having received high doses of ¹³¹I. It can be theorized that the inflammatory process associated with sialadenitis secondarily involved the facial nerve as it passed through the parotid. After remission of the acute inflammation, the facial palsy resolved.

Infection

Oral candidiasis has been reported after the use of ¹³¹I [42]. The fungal infection is facilitated by the reduced salivary flow that follows secretory cell injury from high ¹³¹I dosages. Xerostomia is a known cause of such a fungal infection. Clotrimazole troches function as effective therapeutic agents to combat candidiasis.

Caries

Saliva, through its buffering power, serves to protect the dentition from dental decay. Clinical substantiation of this function is derived from the rampant caries that develop in association with the marked xerostomia after cancericidal doses of external beam radiation to the oral cavity. Walter et al. [43] report high-dose radioiodine treatment can impair the long-term dental health, depending on the cumulative radioiodine activity and individual salivary gland radioiodine uptake. They report that the risk of caries increased with postradioiodine xerostomia (% increase: 98.8), and the long-term risk for tooth extractions increased with increasing cumulative radioiodine treatments (% increase: 8.14/GBq). Fluoride therapy in the form of topical fluoride applications, fluoride mouthwashes, and fluoride toothpaste can prevent the onset of any such radiation-related caries.

Salivary Gland Neoplasms

Because radiation can be carcinogenic, the incidence of salivary neoplasms after ¹³¹I therapy has been investigated. A small but statistically meaningful neoplastic increase years after ¹³¹I therapy has been demonstrated [44–47]. Recent study reports significantly greater risk of salivary gland malignancies than that expected in the general population for patients treated with radioiodine (observed/excess risk: 2.72; 95% CI 1.48–4.56) [47]. Reports include the development of pleomorphic adenoma [35], non-Hodgkin’s lymphoma [48], and mucoepidermoid carcinoma [49–51]. Although definitive evidence is scant regarding neoplastic change, its occurrence would seem to be in direct proportion to the dosage of ¹³¹I.

Strategies for Prevention and Treatment

Rather than accepting the salivary gland damage produced by ¹³¹I, the use of sour candy [1, 4] or lemon juice [28] has been recommended to increase salivation during ¹³¹I administration in an attempt to reduce salivary gland damage. These interventions increase salivary flow and thereby decrease both the transit time of ¹³¹I through the parotid and the salivary ¹³¹I concentration. However, whether this results in a decrease in the overall salivary gland exposure to ¹³¹I is unknown. Transit time through the salivary glands can also be decreased with the cholinergic drugs pilocarpine or cevimeline using an empiric 5-day dosage regimen (2 days before, the day of, and 2 days after ¹³¹I treatment). As a supplement, sugarless sour candy can be used at the time of treatment. Regrettably, there are no studies that have investigated the long-term efficacy of salivary stimulants (sour candy and/or cholinergic medications) in preventing salivary gland damage in patients receiving radioactive iodine. However, Nakada et al. [52] have suggested that the administration of sialagogues within 24 h of administration of either an ablative or therapeutic prescribed treatment with ¹³¹I may be associated with an increased incidence of side effects in the salivary glands (e.g., sialoadenitis, xerostomia). One of the mechanisms they propose is that the sialagogues increase saliva flow and blood flow to the salivary glands. They propose this in turn delivers more ¹³¹I to the salivary glands, resulting in greater uptake of ¹³¹I in the salivary glands than if no sialagogues had been given. However, Van Nostrand et al. [53] demonstrated a decrease of ¹³¹I uptake in the salivary glands using lemon juice during the 24-h period after ¹³¹I treatment and a potential reduction of the radiation-absorbed dose with administration of sialagogues. The timing of administration of sialagogues for reduce salivary gland damage after ¹³¹I therapy is still controversial.

Intravenous amifostine, an organic thiophosphate, is a recent addition to the drug armamentarium to combat the effects of irradiation [54–57]. Within the tissues, amifostine undergoes dephosphorylation to its active metabolite WR-1065. Alkaline phosphatase, present in all tissues, is necessary for this change. The conversion is more effective in the alkaline environment of normal tissue rather than the acid environment of tumor tissue. In addition, the concentration of alkaline phosphatase is 100 times greater in normal tissue than in tumor tissue [44]. Once the WR-1065 becomes available, it acts as a scavenger of oxygen-free radicals, which are the cause of radiation induced tissue damage. A double-blind scintigraphic study examined the effect of amifostine on salivary gland function in 25 patients after amifostine infusion and 25 patients who received a placebo prior to ¹³¹I therapy [54]. In conjunction with amifostine therapy, all 50 patients received salivary stimulation with ascorbic acid and anti-inflammatory therapy with an extremely high dose of dexamethasone (40 mg). One year after the ¹³¹I therapy, parotid and submandibular function was reduced by 40% in the placebo group and remained unchanged in the amifostine group. The one amifostine complication encountered was a decrease in mean blood pressure, which necessitated a temporary suspension of the infusion. Regardless of the safety record, there is some hesitancy to prescribe amifostine because many practitioners are not convinced that the amifostine does not inhibit the efficacy of radioiodine.

Patients should be made aware of the salivary gland damage that follows ¹³¹I therapy for thyroid cancer. The need for lifelong secondary prevention must be understood by the patient. Emphasis should be placed on the need to preserve salivary flow with glandular massage and to practice caution when anticholinergic drugs are used. Avoidance of any form of dehydration and the maintenance of an acceptable daily fluid intake must be impressed on the patient.

Although attention is legitimately directed toward achieving a cancer cure with the ¹³¹I, procedures should be implemented to negate the patient distress that is encountered because of the harmful effect of ¹³¹I on salivary glands. The available techniques to prevent or diminish such injuries should be part of the practitioner’s knowledge base. In addition, early recognition and treatment of sialadenitis serve to lessen patient morbidity.

Treatment of ¹³¹I-induced sialadenitis is typically symptomatic. Aggressive, external massage of salivary glands has been advised to milk out retained saliva and increase salivary lavage. In many cases, nuclear medicine physicians used salivation-inducing snacks, such as lemon candy or chewing gum, before gland massage. Because dehydration may lead to decreased salivary lavage and recurrent exacerbation, nuclear medicine physicians have recommended adequate daily fluid intake and good oral hygiene. If dry mouth continues, cholinergic medication such as pilocarpine is also considered [58]. Steroids or nonsteroidal antiinflammatory drugs can be used for reducing inflammation [32], and drugs containing zinc acetate or vitamin B12 can be used for taste alteration.

The sialoendoscopy method has recently been introduced for intervention in salivary ductal diseases. Indications of interventional sialoendoscopy are recurrent salivary gland swelling without obvious cause such as ductal lesion, ductal stenosis, or ductal dilatation on ultrasonography or sialography. Interventional sialoendoscopy typically results in a high success rate of 82% to 87% [59–61]. Several studies reported interventional sialoendoscopy is an effective tool for the management of patients with ¹³¹I-induced sialadenitis that is unresponsive to medical treatment [62–64]. Symptoms are improved in 50–100% of patients with radioiodine-induced sialadenitis after a single procedure, but major complications and exacerbation of symptoms after the procedure are not reported. This success rate is attributed to the removal of mucus plugs, dilation of strictures, and reduction of inflammation from steroid irrigations at the end of the procedures. Complete ductal stenosis is the most common pathology associated with failed endoscopy [62]. For nonresponders to conservative management, interventional sialoendoscopy is recommended as an alternative method of treatment in selected cases of sialadenitis such as in partial ductal stenosis.